Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Didanosine (ddl) and stavudine (d4T): Absence of peripheral neurotoxicity in rabbits

Some 20 male New Zealand White rabbits (five/group) were given either didanosine (ddl) or stavudine (d4T) at 750 and 1500 mg/kg body weight/day by oral intubation for 24 wk. An additional group was given 300 mg/kg body weight/day zidovudine (AZT) as a negative control. After 13 weeks the high dose of ddl was lowered from 1500 to 1000 mg/kg body weight/day following the death of one rabbit and continued inappetence in the dose group. The rabbits were observed daily, plasma drug levels were monitored, and electrophysiological measurements of peripheral nerve conduction were performed during the study. Additionally, body weight and food intake were recorded, and clinicopathological parameters were evaluated. Sections of selected peripheral nerves, and dorsal and ventral spinal nerve roots were examined by light and transmission electron microscopy. Although peripheral neuropathy has been reported in rabbits with the nucleoside analogue zalcitabine (ddC), based on clinical observations, electrophysiological measurements, and light and electron microscopy, no evidence of peripheral neurotoxicity was observed in rabbits given either ddl or d4T.     

Investigation of synthetic Escherichia coli heat-stable enterotoxin as an immunogen for swine and cattle.

In its native form Escherichia coli heat-stable enterotoxin (STa) is nonantigenic; however, neutralizing antibodies are elicited in animals vaccinated with toxin-carrier conjugates. To study the immunogenicity of STa, peptides STa1-18 and STa5-18 were synthesized, characterized, and conjugated to carrier proteins. Pregnant gilts and heifers were hyperimmunized with the respective conjugates. Following parturition neonates were challenged with virulent E. coli (K99+ STa+). Peptides coupled to ovalbumin and emulsified with Freund adjuvant elicited antibodies that neutralized toxin-induced fluid accumulation in suckling mice. Peptides coupled to particulate carriers, with or without muramyl dipeptide adjuvant, failed to induce a measurable response. Peak antibody levels in sera were observed following three doses of conjugate and persisted for several weeks. The serological response in cattle was superior to that observed in swine; however, antibody levels in porcine colostrum were higher than those observed in cattle. Clinical observations of neonates from vaccinated dams indicated that passively obtained antibody provided partial protection from disease, but not as complete as that demonstrable with whole cell bacterins that induce antibody to pili. However, the data suggest the potential for utility of synthetically prepared antigens.     

A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice

Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic alpha-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for beta-catenin. Sequencing of the tumor DNA encoding beta-catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.     

Etude des anastomoses entre la veine rénale gauche et les plexus intra-rachidiens

Résumé Des anastomoses entre la veine rénale gauche et les plexus rachidiens existent dans environ 80% des cas (16 cas sur 20); elles sont importantes dans 25% des cas (5 cas). Le siège de leur origine est fixe: le plexus du trou de conjugaison de l'espace L1–L2 reçoit généralement ces voies anastomotiques.Ces anastomoses ont une grande importance, puisqu'elles constituent la seule voie collatérale de sûreté du rein dans 7 cas sur 20. Leur hypertrophie, dans certains cas pathologiques, peut être responsable de troubles neurologiques par compression, réversibles après ligature des anastomoses hypertrophiées.     

Use of VA ECMO and percutaneous palliation of ductal dependent coarctation in a neonate with trisomy 21 and COVID-19 pneumonia

We present a case of a neonate with trisomy 21, ductal-dependent aortic coarctation, and severe respiratory failure secondary to coronavirus disease 2019 (COVID-19) pneumonia. The neonate was managed with venoarterial extracorporeal membrane oxygenation (VA ECMO), palliative stenting of the coarctation, and a vascular plug occlusion of a large patent ductus arteriosus. The patient was successfully weaned off extracorporeal membrane oxygenation (ECMO). The patient is currently awaiting a definitive surgical repair in the near future.     

Familial Duane's retraction syndrome.

BACKGROUND: Duane's retraction syndrome (DRS) has been described as a clinical entity for more than a century. Although the majority of cases occur spontaneously, some cases of DRS are inherited. CASE REPORTS: A young Romanian boy with a known left abduction deficit was determined to have DRS. On thorough examination of other family members, it was discovered that his younger brother and father also had the syndrome. Clinical findings of the affected family members are described. RESULTS: All three family members showed left esotropia in primary gaze, along with a compromised ability to turn the left eye outward. They also demonstrated an anomalous head turn to the left, and mild narrowing of the palpebral fissure and retraction of the globe on adduction. These are all classic signs of unilateral DRS. CONCLUSION: These findings provide further evidence of an autosomal dominant mode of inheritance in some cases of DRS.     

Time course of and effect of dietary iron level on iron incorporation into erythrocytes by infants

As a part of our effort to explore various aspects of ferrokinetics in infancy, the present study was designed to determine the timing of entry of an orally ingested iron isotope into circulating erythrocytes, and the effect of the level of dietary iron [0.3 mg/100 kcal (418.4 kJ) vs. 1.8 mg/100 kcal] after isotope administration on erythrocyte incorporation of the isotope. We administered the stable isotope, (58)Fe, orally to 56-d-old and 168-d-old infants. All infants were fed a low-iron formula (LF) before and until 5 h after isotope administration. Thereafter, half the infants were fed a formula high in iron (HF group) while the remaining infants continued to receive the LF (LF group) for an additional 28 d. The quantity of (58)Fe in circulating erythrocytes increased from 14 to 28 d after isotope administration was nearly constant from 28 through 84 d of age (plateau value) and decreased between 84 and 112 d. Erythrocyte incorporation of (58)Fe was greater by the 168-d-old infants than by the 56-d-old infants, presumably because of the lesser iron stores of the older infants. In the 56-d-old infants, erythrocyte incorporation of (58)Fe was greater by the LF than by the HF group, but this difference was not significant in the 168-d-old infants. Thus, at least in younger infants, the level of iron intake after administration of an iron isotope affects erythrocyte incorporation of the isotope. The fact that less isotope was present in erythrocytes 112 d than 84 d after administration indicates that the life span of erythrocytes of infants, even beyond the immediate newborn period, is less than the 120-d life span of erythrocytes in the adult.